This application, titled "Treatment Implications of Trauma Memory Modulation for PTSD &Alcohol Dependence", primarily addresses broad Challenge Area (15) Translational Science and specific Challenge Topic, 15-AA-104: PTSD and Alcohol Dependence;it secondarily addresses broad Challenge Area (01) Behavior, Behavioral Change, and Prevention and specific Challenge Topic, 01-AA-105: Mechanisms of Behavior Change. Introduction: The co-occurrence of posttraumatic stress disorder (PTSD) and alcohol dependence (AD) is one of the most frequently occurring and debilitating mental health comorbidities. Several perspectives on the nature of the relationship between these disorders have been forwarded and one of the most widely recognized conceptualizations holds that PTSD sufferers often use alcohol as a means of dampening the emotional distress associated with PTSD. Over time, the alcohol use escalates into AD. From a behavior analytic perspective, the mechanism of action for the development of pathological drinking is the escape or avoidance it provides from the emotional distress of PTSD. An important implication of this conceptual understanding of the PTSD and AD interrelationship is that effective treatment of PTSD should yield significant reductions in motivation to drink and drinking behavior. There is a developing clinical literature that supports this assumption and the present study will contribute further to it by examining the impact of the [unreadable]-adrenergic blocker propranolol on emotional distress, craving and other responses to trauma- and alcohol-related cues and on alcohol use and PTSD symptoms. The impetus for the proposed proof-of-concept translational research comes from both basic science and a developing clinical science literature that suggests the strategic administration of the [unreadable]-adrenergic blocker propranolol after recalling the memory of a fear-inducing event(s) can result in an attenuation of the negative emotion and arousal of memories for the fear-inducing events. This effect is presumed to result from propranolol's ability to quell the adrenergic activity involved in the reconsolidation of memories for the fear-inducing event(s) after they are recalled. Approach: This study will employ 50 PTSD/AD comorbid participants to investigate the effects of propranolol vs. placebo, administered immediately after exposure to scripted imagery of a crime-related trauma, on the subjective, physiological and stress responses occurring during a subsequent test session consisting of exposure to the trauma scripted imagery and also the sight and smell of the participant's preferred alcoholic beverage. Participants will be randomly assigned to receive either 40 mg of propranolol or placebo (double-blinded) immediately after the first of two trauma-imagery cue exposure sessions scheduled to occur on consecutive days of an inpatient stay at MUSC's Clinical and Translational Research Center (CTRC). The first session will serve as a retrieval session during which trauma script-imagery cue exposure will elicit retrieval and reconsolidation of memories of the participant's index trauma;the second session will be a test session to examine the potential modulatory role of propranolol on the reconsolidated memories putatively elicited during the retrieval session. It is posited that changes in craving, physiological and/or stress reactivity during the test session will reflect propranolol's effects on memory reconsolidation processes elicited by trauma cue exposure in the retrieval session. Measures of subjective craving, emotion, physiological arousal (e.g., heart rate) and stress (e.g., cortisol) reactivity will be obtained at baseline, during and after the trauma cue presentation in session 1 and the trauma and alcohol cue presentations in the test session. The durability of any observed treatment effects will be assessed in a follow-up laboratory session performed 14 days following discharge from the inpatient stay and which will be identical to the test session. Treatment effects on both alcohol use during preceding 14 days and severity of PTSD symptoms will also be assessed. Implications: This research will directly address the challenge area of translational science in PTSD and AD by extending basic neuroscience findings on memory modulation to a human laboratory proof-of-concept analog with substantial potential clinical benefit for members of this at risk, dually afflicted population. Positive findings could energize future studies to define the optimal parameters under which propranolol could be used in prolonged exposure therapy (PTSD treatment gold standard) to enhance reduction of both PTSD-related anxiety and drinking. Additionally, the clinical benefits of cue exposure therapy for AD (i.e., systematic exposure to alcohol-related cues) might be enhanced by using propranolol to interfere with memory reconsolidation of the cue->alcohol associations that subserve craving for alcohol. In fact, both types of exposure therapy might be synergistically enhanced by strategic application of propranolol following retrieval of both trauma-memories and memories for cue->alcohol associations. The proposed research will also address the topic area of mechanisms of behavior change within the challenge area of behavior, behavioral change, and prevention by a) contributing to a literature base that suggests PTSD has a primary causal role in PTSD/AD comorbidity because PTSD is the source of the aversive emotion/arousal which, when dampened by alcohol use, provides the negative reinforcement that promotes further use and risk of dependence, and b) empirically assessing the role of the [unreadable]-adrenergic system in the trauma-related memory processes that mediate the interface between PTSD and AD. This innovative translational research endeavor will employ an established cue reactivity/exposure methodology to assess the therapeutic potential of an untested and potentially promising adjunctive pharmacotherapy for one of the most prevalent and intractable mental health comorbidities, PTSD and alcohol dependence. It is hoped the results of this proof-of-concept investigation will lead to the development of a pharmacological treatment element that will enhance the outcomes of exposure-based treatment for individuals with PTSD and alcohol dependence and be generalizable to other co-occurring substance use disorders.